Kidney transplantation is the preferred treatment modality for patients with end-stage renal disease (ESRD). Compared to dialysis, transplantation leads to improved quality of life, longer patient survival and considerable cost reductions. Progress in medical therapy has dramatically improved short-term survival of deceased donor kidney transplants (DDKT), 92% of grafts function beyond one year. However, long-term results remain poor with 10 year graft survival rates of 45% and 33.8% in European Americans (EAs) and African Americans (AAs), respectively. New tools to improve long-term graft survival are urgently needed. Risk variants in the apolipoprotein L1 (APOL1) nephropathy gene and caveolin-1 (CAV1) gene in kidney donors shorten graft survival after transplantation. This provides strong evidence that gene variants associated with kidney disease impact transplant outcomes. The overarching goal of this proposal is to systematically search for genetic and environmental factors impacting graft survival after DDKT. We propose to test variants in 56 replicated nephropathy susceptibility loci from kidney donors for association with long-term kidney transplant graft survival. Interactive effects of gene variants with each other and with environmental stressors associated with nephropathy will be performed. Finally, gene expression will be carried out in healthy human kidney cells that contain risk variants that associate with kidney graft survival to better understand how gene variants cause kidney disease. The present analyses will be conducted in two phases: a Discovery phase involving genetic data from 2,500 (2000 EAs, 500 AAs) independent donor-kidney DNA samples, followed by a Replication phase where an additional 1,000 samples (800 EAs, 200 AAs) will be analyzed. A combined analysis will be performed to finalize parameter estimates and identify variants to be followed up in gene expression analyses. The 56 tested variants all reached genome-wide statistical significance in prior studies and many have been replicated. They have improved our understanding of the pathogenesis of kidney disease. However, most have relatively weak effects and low predictive ability limiting their clinical utility. We propose a systematic approach, analyzing nephropathy genes identified in genome-wide association studies in kidney transplantation. After transplantation, kidneys are stressed by prolonged lack of organ perfusion and exposure to nephrotoxic medications. These factors likely provide the contrast necessary to detect contributors to kidney allograft survival. This work is likely to improve outcomes after kidney transplantation and would allow meaningful translation of genetic association results in an important clinical realm.